Rett syndrome (RTT) is an X-linked disorder caused by loss of function mutations in the MECP2 gene. RTT is a leading cause of mental retardation with autistic features in girls and is characterized by loss of acquired cognitive, motor and social skills. MECP2 mutations have also been shown to cause non-syndromic forms of mental retardation in both males and females. The methyl-CpG binding protein 2 (MeCP2) is a transcriptional represser that binds to methylated CpG dinucleotides. The molecular events resulting from dysfunction of MeCP2 and causing the neurologic deficits of RTT are unknown. Mecp2308/Y mutant mice generated in Dr. Zoghbi's lab are an excellent model to study the biological basis of this disorder. Dietary methyl donors can significantly modify the phenotype of these mice. This proposal aims to understand the cognitive and motor deficits of RTT by studying behavioral and functional abnormalities in the brain of mutant mice and investigating molecular mechanisms by which loss of MeCP2 function causes the RTT phenotype. It is based on the hypothesis that loss of MeCP2's function causes altered transcriptional regulation and abnormal expression of neuronal proteins required for synaptic plasticity. The specific aims are to: (1) Study Mecp2308/Y mice for learning and memory deficits; (2) Characterize electrophysiological abnormalities of synaptic plasticity in cortical and subcortical areas of the brain in mutant mice; (3) Identify genes that are abnormally expressed in affected brain regions of Mecp2308/Y mice and discover transcriptional changes associated with phenotypic improvement in response to a low methyl donor diet. These studies will begin to shed light on the cellular and molecular abnormalities of RTT and the role of methyl donors and DNA methylation in neuronal function. Key molecular regulators of cognition and motor function as well as modifiers of these neurologic phenotypes will be identified. These molecules will provide targets for the selection of rational treatment strategies in RTT and may be relevant to the study of neurologic diseases with overlapping phenotypes, such as autism and movement disorders.